FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

FLT3 abnormalities are negative prognostic markers in acute leukemia. Infant leukemias are a subgroup with frequent MLL (KMT2A) rearrangements, FLT3 overexpression and high sensitivity to cytarabine, but dismal prognosis. Cytarabine is transported into cells by Human Equilibrative Nucleoside Transporter-1 (hENT1, SLC29A1), but the mechanisms that regulate hENT1 in acute leukemia have been scarcely studied.

We explored the expression and functional link between FLT3 and main cytarabine transporters in 50 pediatric patients diagnosed with acute lymphoblastic leukemia and MLL rearrangement (ALL-MLL+) and other subtypes of leukemia, and in leukemia cell lines.

A significant positive correlation was found between FLT3 and hENT1 expression in patients. Cytarabine uptake into cells was mediated mainly by hENT1, hENT2 and hCNT1. hENT1-mediated uptake of cytarabine was transiently abolished by the FLT3 inhibitor PKC412, and this effect was associated with decreased hENT1 mRNA and protein levels. Noticeably, the cytotoxicity of cytarabine was lower when cells were first exposed to FLT3 inhibitors (PKC412 or AC220), probably due to decreased hENT1 activity, but we observed a higher cytotoxic effect if FLT3 inhibitors were administered after cytarabine.

FLT3 regulates hENT1 activity and thereby affects cytarabine cytotoxicity. The sequence of administration of cytarabine and FLT3 inhibitors is important to maintain their efficacy.

Related collections

Most cited references 49

Record: found
Abstract: found
Article: not found

A critical review of which children with acute myeloid leukaemia need stem cell procedures.

Henrik Hasle (2014)

The last decades have seen parallel improvements in chemotherapy-based and haematopoietic stem cell transplantation (HSCT) regimens for acute myeloid leukaemia (AML) in children. There has been no consensus on indication for HSCT. Reserving HSCT for high-risk and relapsed patients spare many patients from the long-term toxicity of this treatment. The results of matched unrelated donor HSCT equal family donor transplantation and the presence of a matched sibling should no longer be a transplant indication. Minimal residual disease measured by flow cytometry may identify poor responders benefitting from HSCT in first complete remission (CR1) and those with a favourable response to induction therapy who do not need HSCT even with adverse cytogenetic aberrations. FLT3-internal tandem duplication without NPM1 mutation has a very high relapse rate despite favourable response and HSCT is indicated in CR1 in these cases. Finding the optimal indications for HSCT is a delicate balance between risk of relapse and late effects.

0 comments Cited 20 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Human pancreatic cancer stem cells are sensitive to dual inhibition of IGF-IR and ErbB receptors

Nerea Urtasun, Anna Vidal-Pla, Sandra Pérez-Torras … (2015)

Background Pancreatic ductal adenocarcinoma is a particularly challenging malignancy characterized by poor responsiveness to conventional chemotherapy. Although this tumor frequently overexpresses or possesses constitutively activated variants of IGF-IR and EGFR/Her-2, clinical trials using inhibitors of these receptors have failed. ErbB receptors have been proposed as one mechanism involved in the resistance to IGF-IR inhibitors. Therefore, combined treatment with inhibitors of both IGF-IR and ErbB receptors would appear to be a good strategy for overcoming the emergence of resistance. Methods Sensitivity of cells to NVP-AEW541 and lapatinib in single or combination treatment was assessed by MTT or WST-8 assays in a panel of human pancreatic cancer cell lines and cancer stem cells. Tumorspheres enriched in cancer stem cells were obtained from cultures growing in non-adherent cell plates. The effects on cell signalling pathways were analyzed by Western blot. Results We found that combined treatment with the IGF-IR and EGFR/Her-2 inhibitors NVP-AEW541 and lapatinib, respectively, synergistically inhibited pancreatic cancer cell growth. Analysis at molecular level argued in favor of cross-talk between IGF-IR and ErbBs pathways at IRS-1 level and indicated that the synergistic effect is associated with the total abolishment of Akt, Erk and IRS-1 phosphorylation. Moreover, these inhibitors acted synergistically in tumorsphere cultures to eliminate cancer stem cells, in contrast to their resistance to gemcitabine. Conclusions Taken together, these data indicate that simultaneous blockade of IGF-IR and EGFR/Her-2 using NVP-AEW541 and lapatinib may overcome resistance in pancreatic cancer. Thus, the synergy observed with this combined treatment indicates that it may be possible to maximize patient benefit with the appropriate combination of currently known anticancer agents. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1249-2) contains supplementary material, which is available to authorized users.

0 comments Cited 9 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Translocation of nucleoside analogs across the plasma membrane in hematologic malignancies.

Paula X Fernandez-Calotti, Dolors Colomer, Marçal Pastor-Anglada (2011)

Nucleoside analogs are currently used in the treatment of various hematologic malignancies due to their ability to induce apoptosis of lymphoid cells. For nucleoside-derived drugs to exert their action, they must enter cells via nucleoside transporters from two gene families, SLC28 and SLC29 (CNT and ENT, respectively). Once inside the cell, these drugs must be phosphorylated to their active forms. In contrast, some members of the ATP-binding cassette (ABC) protein family have been identified as responsible for the efflux of the phosphorylated forms of these nucleoside-derived drugs. Here, we review the main nucleoside analogs used in hematologic malignancies and focus especially on those that are currently used in chronic lymphocytic leukemia (CLL). Moreover, we discuss the pharmacological profile of the nucleoside transporters, which determines the bioavailability of and cell sensitivity to these nucleoside-derived drugs. We also discuss the expression of nucleoside transporters and their activities in CLL as well as the possibility of modulating these transporter activities as a means of modulating intracellular drug availability and, consequently, responsiveness to therapy.

0 comments Cited 7 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 2 August 2016

Publication date (Electronic): 6 July 2016

Volume: 7

Issue: 31

Pages: 49786-49799

Affiliations

¹ Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain

² National Biomedical Research Institute on Rare Diseases (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain

³ Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine (IBUB), Barcelona, Spain

⁴ Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain

⁵ Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain

⁶ Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain

Author notes

Correspondence to: Albert Català, acatala@ 123456hsjdbcn.org

Marçal Pastor-Anglada, mpastor@ 123456ub.edu

Article

Publisher ID: 10448

DOI: 10.18632/oncotarget.10448

PMC ID: 5226548

PubMed ID: 27391351

SO-VID: 76b61727-17c3-4a01-adf0-f2636544d3e8

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

Read this article at

Abstract

Related collections

Karger: Oncology

Most cited references 49

A critical review of which children with acute myeloid leukaemia need stem cell procedures.

Human pancreatic cancer stem cells are sensitive to dual inhibition of IGF-IR and ErbB receptors

Translocation of nucleoside analogs across the plasma membrane in hematologic malignancies.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 621

Cited by 5

Most referenced authors 364